Molecular Dynamics Analysis of Binding of Kinase Inhibitors to WT EGFR and the T790M Mutant,Journal of Chemical Theory and Computation

当前位置： X-MOL 学术 › J. Chem. Theory Comput. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Molecular Dynamics Analysis of Binding of Kinase Inhibitors to WT EGFR and the T790M Mutant
Journal of Chemical Theory and Computation ( IF 5.7 ) Pub Date : 2016-04-04 00:00:00 , DOI: 10.1021/acs.jctc.5b01221
Jiyong Park ₁ , Joseph J. McDonald ₂ , Russell C. Petter ₂ , K. N. Houk ₁

Affiliation

Epidermal growth factor receptor (EGFR) inhibitors interrupt EGFR-dependent cellular signaling pathways that lead to accelerated tumor growth and proliferation. Mutation of a threonine in the inhibitor binding pocket, known as the “gatekeeper”, to methionine (T790M) confers acquired resistance to several EGFR-selective inhibitors. We studied interactions between EGFR inhibitors and the gatekeeper residues of the target protein. Thermodynamic integration (TI) with Amber14 indicates that the binding energies of gefitinib and AEE788 to the active state of the T790M mutant EGFR is 3 kcal/mol higher than to the wild type (WT), whereas ATP binding energy to the mutant is similar to the WT. Using metadynamics MD simulations with NAMD v2.9, the conformational equilibrium between the inactive resting state and the catalytically competent activate state was determined for the WT EGFR. When combined with the results obtained by Sutto and Gervasio, our simulations showed that the T790M point mutation lowers the free energy of the active state by 5 kcal/mol relative to the inactive state of the enzyme. Relative to the WT, the T790M mutant binds gefitinib more strongly. The T790M mutation is nevertheless resistant due to its increased binding of ATP. By contrast, the binding of AEE788 to the active state causes a conformational change in the αC-helix adjacent to the inhibitor binding pocket, that results in a 2 kcal/mol energy penalty. The energy penalty explains why the binding of AEE788 to the T790M mutant is unfavorable relative to binding to WT EGFR. These results establish the role of the gatekeeper mutation on inhibitor selectivity. Additional molecular dynamics (MD) simulations, TI, and metadynamics MD simulations reveal the origins of the changes in binding energy of WT and mutants.

中文翻译：

激酶抑制剂与WT EGFR和T790M突变体结合的分子动力学分析

表皮生长因子受体（EGFR）抑制剂可中断EGFR依赖的细胞信号传导途径，从而加速肿瘤的生长和扩散。抑制剂结合袋中的苏氨酸突变为蛋氨酸（T790M），使之获得获得的对几种EGFR选择性抑制剂的抗性。我们研究了EGFR抑制剂与靶蛋白的关守残基之间的相互作用。与Amber14的热力学整合（TI）表明，吉非替尼和AEE788与T790M突变体EGFR活性状态的结合能比野生型（WT）高3 kcal / mol，而与突变体的ATP结合能与WT。使用NAMD v2.9的元动力学MD模拟，对于WT EGFR，确定了非活性静止状态和催化活性活化状态之间的构象平衡。当结合Sutto和Gervasio的结果时，我们的模拟结果表明T790M点突变使活性状态的自由能相对于酶的非活性状态降低了5 kcal / mol。相对于WT，T790M突变体与吉非替尼的结合更牢固。然而，T790M突变由于其与ATP的结合增加而具有抗性。相比之下，AEE788与活性状态的结合会导致与抑制剂结合口袋相邻的αC-螺旋构象变化，从而导致2 kcal / mol的能量损失。能量损失解释了为什么AEE788与T790M突变体的结合相对于与WT EGFR的结合是不利的。这些结果确定了关守突变对抑制剂选择性的作用。其他分子动力学（MD）模拟，TI和元动力学MD模拟揭示了WT和突变体结合能变化的起源。

更新日期：2016-04-04

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南